1. Field of the Invention
This invention relates to a novel process that permits the unexpectedly efficient and convenient preparation of thromboxane A.sub.2 inhibiting (.+-.)7-[3.alpha.-[1-[[(phenylamino)thioxomethyl]hydrazono]ethyl]-1.alpha. ,4.alpha.-bicyclo[2.2.1]hept-2.beta.-yl]heptenoic acids (hereinafter called "bicycloheptenoic acids") of Example 2 of U.S. Pat. No. 4,596,823, as well as its geometric isomer. The process is easily and conveniently adapted to the synthesis of a great number of derivatives of the subject bicycloheptenoic acids as disclosed in U.S. Pat. No. 4,596,823, having the general formula ##STR1## from compounds of the general formula ##STR2## in which R.sub.1 is a group of the formula R'-COQ where R' is selected from the group consisting of --(CH.sub.2).sub.j --
where j is an integer from 4 to 8; and --CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.m --
where m is an integer from 1 to 5; and COQ is carboxy, a physiologically acceptable carboxylate salt (including such specific examples as alkali metals such as sodium, quaternary ammonium ions, or amines such as tris, i.e. 2-amino-2-hydroxymethylpropane 1,3-diol), a C.sub.1 -C.sub.5 alkyl ester or CONHSO.sub.2 CH.sub.3 ;
R.sub.2 is selected from the group consisting of hydrogen, C.sub.1-10 aliphatic hydrocarbon groups, and C.sub.1-10 aliphatic hydrocarbon groups substituted by Ar, OAr or SAr, where Ar represents a phenyl, napthyl, fluorenyl, dibenzocyclohexyl, dibenzocycloheptyl, pyridyl, benzthiazolyl, dihydrobenzthiazolyl, N-methyldihydrooenzthiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyldihydrobenzoxazolyl group or such a group substituted by one or more substituents selected from C.sub.1-10 alkoxy, halogen, C.sub.1-10 halogen-substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and C.sub.1-10 alkyl groups; and R is a group --OR.sub.3, --OR.sub.4, --A--R.sub.3 or --N.dbd.R.sub.5 in which A is --NH--, --NHCO-- and --NHCONH--, --NH CO CH.sub.2 N(R.sub.6)--, --NH SO.sub.2 --, or --NH CS NH-- and wherein R.sub.3 is a C.sub.1-10 aliphatic hydrocarbon group, a group Ar or a C.sub.1-10 aliphatic hydrocarbon group substituted by one or more groups selected from Ar, OAr and SAr; R.sub.4 is substituted through an oxygen atom by a C.sub.1-10 aliphatic hydrocarbon group which is itself substituted by one or more groups Ar; R.sub.5 is a C.sub.1-10 alphatic hydrocarbon group, a group Ar', where Ar' represents a fluorenylidene, dibenzocyclohexylidene, dibenzocycloheptylidene, dihydrobenzthiazolylidene, N-methyldihydrobenzthiazolylidene, dihydrobenzoxazolylidene or N-methyldihydrobenzoxazolylidene group or such a group substituted on a benzene ring or rings thereof by one or more substituents selected from C.sub.1-10 alkoxy, halogen, C.sub.1-10 halogen-substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and C.sub.1-10 alkyl groups, or a C.sub.1-10 aliphatic hydrocarbon group substituted by one or more groups selected from Ar, OAr and SAr; and R.sub.6 is hydrogen, a C.sub.1-10 aliphatic hydrocarbon group, a group Ar or a C.sub.1-10 aliphatic hydrocarbon group substituted by one or more groups selected from Ar, OAr and SAr. These derivatives are more fully described in U.S. Pat. No. 4,596,823, the disclosure of which is incorporated herein by reference.
More specifically, this invention relates to a process for preparing bicycloheptenoic acids of Formula I in improved overall yield and purity by reacting a cyclic hemiacetal with a phosphonium ylide derived from an omega substituted fatty acid, oxidizing the resultant product to the corresponding ketone, and forming a hydrazone from the corresponding ketone.
This invention also relates to novel intermediates employed in the preparation of the thromboxane A.sub.2 inhibiting bicycloheptenoic acid derivatives of Formula I.